rs139912214

Positions:

chr1-47281003-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001048166.1(STIL):c.1455G>C(p.Leu485Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,614,076 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 5 hom. )

Consequence

STIL
NM_001048166.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:10

Conservation

PhyloP100: 0.337

Variant links:

Genes affected

STIL (HGNC:10879): (STIL centriolar assembly protein) This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate V-(D)-J recombination events. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

STIL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040679574).

BP6

Variant 1-47281003-C-G is Benign according to our data. Variant chr1-47281003-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 160052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47281003-C-G is described in Lovd as [Pathogenic]. Variant chr1-47281003-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIL	NM_001048166.1 linkuse as main transcript	c.1455G>C	p.Leu485Phe	missense_variant	12/17	ENST00000371877.8	NP_001041631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIL	ENST00000371877.8 linkuse as main transcript	c.1455G>C	p.Leu485Phe	missense_variant	12/17	1	NM_001048166.1	ENSP00000360944	P5	Q15468-2

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

293

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00276

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00219

AC:

551

AN:

251306

Hom.:

AF XY:

0.00215

AC XY:

292

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00884

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00209

AC:

3056

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1525

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.00918

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00222

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152248

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00276

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00285

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00213

AC:

259

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2024	The p.Leu438Phe variant in STIL is classified as likely benign because it has been identified in 0.9% (267/29604) of Ashkenazi Jewish chromosomes, 0.4% (29/6060) of Middle Eastern chromosomes and 0.3% (156/60012) of Admixed American chromosomes, including 6 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 17, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	STIL: BP4, BS2 -

Abnormal brain morphology

Pathogenic:1

Likely pathogenic, flagged submission

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2013

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Microcephaly 7, primary, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

T;.;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.73

T;T;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.0041

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

N;.;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.091

T;.;T;T;T

Sift4G

Benign

0.29

T;T;T;T;.

Polyphen

0.058

B;.;B;B;B

Vest4

0.030

MutPred

0.092

Loss of glycosylation at S484 (P = 0.1331);.;Loss of glycosylation at S484 (P = 0.1331);Loss of glycosylation at S484 (P = 0.1331);.;

MVP

0.32

MPC

0.13

ClinPred

0.00071

GERP RS

-0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.042

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over